tbuckley/cabot-search huggingface dataset:
Abstract 3440: Novel <i>in vitro</i> TME platform for rapid cancer therapeutic and target discovery
Authors: Polina R. Matre, Byung-Kwon Choi, Oliver Delgado, John K. Westwick
Journal: Cancer Research (2022)

Abstract The tumor microenvironment (TME) plays an important role in malignances as tumors react with a multitude of changes and microenvironmental cues. TME components modulate tumor profiles and treatment responses, thereby affecting sensitivity to anti-cancer agents. The limited clinical success of therapeutics, including immunotherapies, emphasizes an unmet need to identify new targets and develop preclinical platforms to accelerate anti-cancer drug discovery. Although in vitro methods are essential in early drug development, standard approaches, which do not capture the complexity of TME, have been historically favored for both discovery and evaluation of potential therapeutics. Resonant's IMPACT TME platform couples proprietary high-fidelity TME models with deep data-driven analytics for rapid and cost-effective discovery of novel targets and antibody-based therapeutics. Target and candidate selection is based upon a biology-forward approach driven by live animal immune systems and functional screening prior to target identification. Identified candidates are then prioritized via integration of publicly available information with internal functional and multi-omic data. Resultant targets display attributes, such as tumor selectivity and immune-modulatory capabilities, that are amenable to several therapeutic modalities, including antibody-drug conjugates (ADCs) and bispecifics. To date, Resonant has interrogated a variety of solid tumor types and thousands of candidates resulting in an expanding library of actionable antibodies and targets. Representative examples of in vitro and in vivo efficacy of selected candidates derived from the IMPACT TME platform are presented, highlighting their individual potential and validating the Resonant approach. As technological advances transform the landscape of therapeutics, the need for novel targets is burgeoning, and Resonant’s TME-driven platform provides a valuable tool to meet these demands. Citation Format: Polina R. Matre, Byung-Kwon Choi, Oliver Delgado, John K. Westwick. Novel in vitro TME platform for rapid cancer therapeutic and target discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3440.
Abstract 6114: Prognostic value of the tumor-infiltrating lymphocytes in Miller-Payne grade 4 triple-negative breast cancer following neoadjuvant chemotherapy
Authors: Jianli Ma, Yuwei Deng, Dawei Chen, Xiaomei Li, Zhiyong Yu, Haibo Wang, Lei Zhong, Yingjie Li, Chengqin Wang, Xiaoping Zhou, Xiang Li, Qingyuan Zhang, Jinming Yu
Journal: Cancer Research (2022)

Abstract Background Triple-negative breast cancer (TNBC) with pathological complete response after neoadjuvant chemotherapy (NACT) has better prognosis, but there remain uncertainties upon the prognostic judgement for Miller-Payne 4 patients. We evaluated the prognostic correlations with the tumor-infiltrating lymphocytes (TILs) status in Miller-Payne 4 patients. Methods A total of 272 TNBC patients with NACT were assessed as Miller-Payne grade 4/5. Pre-treatment core biopsies from Miller-Payne 4 patients were specifically assessed for TILs with prognostic relevance using standardized methods. The corresponding spatial distributions and components of the TILs were thoroughly analyzed by IMC and proteomic. Results The 5-year disease-free survival (DFS) was 63.8% for Miller-Payne 4 and 83.0% for Miller-Payne 5 (p=0.003), and overall survival (OS) was 71.0% and 85.5% respectively (p=0.007). High TILs were significantly associated with longer DFS (p=0.007) and OS (p=0.004) in Miller-Payne 4/5 patients, and also in the Miller-Payne 4 subgroup (both p=0.016). Spatially, Miller-Payne 4 with good prognosis had an inflamed signature, included dominant T cells surrounding tumor cells with focal infiltrations, limited scattered myeloid-derived cells which were separated from T cells, and reduced suppressive cytokines. Functionally, 109 immunologically effective proteins were upregulated and 76 immunosuppressive components were downregulated, indicating more immunological effective activities. By contrast, Miller-Payne 4 with poor prognosis had an excluded signature. We also observed similar immune signatures in Miller-Payne 5. Conclusion Miller-Payne 4 combined with immunotyping of the TILs could be powerful prognostic indicators for Miller-Payne 4 TNBC with NACT. Citation Format: Jianli Ma, Yuwei Deng, Dawei Chen, Xiaomei Li, Zhiyong Yu, Haibo Wang, Lei Zhong, Yingjie Li, Chengqin Wang, Xiaoping Zhou, Xiang Li, Qingyuan Zhang, Jinming Yu. Prognostic value of the tumor-infiltrating lymphocytes in Miller-Payne grade 4 triple-negative breast cancer following neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6114.
Abstract 1969: Distinctive profiles on immunotherapy responders versus non responders in Chilean gastric cancer patients
Authors: Mauricio P. Pinto, Matias Muñoz Medel, Miguel Córdova Delgado, Ignacio N. Retamal, Patricio Manque, Alejandro Berkovits, Maria Paz Rodriguez, Juvenal A. Rios, Benjamin Garcia-Bloj, Gareth Owen, Marcelo Garrido
Journal: Cancer Research (2022)

Abstract Background: Gastric cancer (GC) is the leading cause of cancer death in Chile, claiming &amp;gt;3,000 lives per year. On April 2021, the US Food and Drug Administration approved the combined use of Nivolumab (immunotherapy) plus chemotherapy as frontline treatment for advanced GC. Unfortunately, as occurs with any therapy, a proportion of treated patients are either unresponsive or display poor responses. Our study sought to obtain a profile of GC patients categorized as responders or non-responders to immunotherapy in order to identify better predictors of response and novel targets for treatment refractory patients. Methods: A total of 50 GC patients were included into our study. Demographic and basic information was obtained from medical records. Additionally, we retrieved information on response to treatment, histological type, PDL1 and HER2 status. Nucleic acid samples were collected from a subset of 45 patients (responders and non-responders) and analyzed by massive analysis of cDNA ends (MACE-seq) assessing 3’ mRNA sequencing. Results: Patients were predominantly male (76%) and advanced stage (III/IV; 98%). Within this subset, 26 were responders and 24 were non-responders. Among clinical variables, body mass index was significantly higher on responders versus non-responders (p=0.026). Among responders, tumors were predominantly located on the gastro-esophagic junction. As expected, responders also displayed a higher prevalence of HER2- and PDL1+. Our 3’ MACE analysis confirmed distinct profiles on responders compared to non-responders. Conclusions: Our findings confirm distinctive profiles among Chilean GC patients categorized as responders or non-responders to immunotherapy. These results could deliver novel markers that may serve as predictors of response to immunotherapy (as an alternative to PDL1) or to identify patients more likely to be refractory to treatment. Future studies should further confirm and validate these findings in a larger sample. Citation Format: Mauricio P. Pinto, Matias Muñoz Medel, Miguel Córdova Delgado, Ignacio N. Retamal, Patricio Manque, Alejandro Berkovits, Maria Paz Rodriguez, Juvenal A. Rios, Benjamin Garcia-Bloj, Gareth Owen, Marcelo Garrido. Distinctive profiles on immunotherapy responders versus non responders in Chilean gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1969.
Abstract 5557: PMC-309, a highly selective anti-VISTA antibody reverses immunosuppressive TME to immune-supportive TME
Authors: Cheon Ho Park, Sang Soon Byun, Jin Yong An, Hyerim Han, Weon Sup Lee
Journal: Cancer Research (2022)

Abstract Purpose: We investigated the pharmacology of PMC-309 in ex vivo or in vivo characterization for the development of the preclinical study. Experimental procedures: Target selectivity: it was measured by SPR assay. Human VISTA expressing CHO k1 cells or CHO k1 mock cells were used in cell binding assay. Target cell analysis: human peripheral blood mononuclear cells (PBMC) containing lymphocyte and myeloid lineage cells were used for target cells analysis with flow cytometry. In vitro T cell activity: human PBMC was employed for the evaluation of T cell activity (IRB #1041107-201703-BR-002-02) and was stimulated with or w/o PMC-309 in the presence of anti-CD3/28 Antibody. In vivo study: MC38 bearing human VISTA knock-in (KI) mice were employed for the assessment of anti-tumor activity of PMC-309. The tumor infiltrated immune cells: Immune cells in the TME were evaluated by immunohistochemistry (IHC) or flow cytometry (FACS) analysis. Statistics: All data were presented as the mean ± SEM and analyzed using one-way ANOVA followed by Dunnett’s multiple comparison tests in Graph pad prism®. ***p&amp;lt;0.001, **p&amp;lt;0.01 and *p&amp;lt;0.05 compared to Control group. Summary of data: PMC-309 binding to VISTA expressing cells is highly selective and the selectivity is maintained even in the low pH conditions that mimic TME. PMC-309 enhances the secretion of IFN-gamma, TNF-alpha, and IL-2 in Mixed Lymphocyte Reaction (MLR) settings. In addition, PMC-309 promoted monocyte differentiation into M1 macrophage that stimulates proinflammatory cytokine secretion of T cells. For the in vivo study, PMC-309 was intravenously administrated in VISTA-KI mice. The tumor growth rate was suppressed in accompanied by a synergistic effect with an anti-PD1 antibody. The anti-tumor activity was associated with enhanced T cell activation, increased secretion of pro-inflammatory cytokines, and increased penetration of cytotoxic T cells, but lowing immune-suppressive MDSC cells into TME as demonstrated with IHC analysis. Conclusions: PMC-309 is a fully human anti-VISTA antibody that targets human VISTA specifically. PMC-309 enhanced both T cell activation and monocyte activation when monocytes were cultured with or without T cells by targeting VISTA. PMC-309 increased the number of T cell infiltration while a decrease of MDSCs in the TME. PMC-309 in combination with chemotherapy or other IO drugs could address highly medical unmet needs from patients with drug resistance to currently available IO treatment options. Citation Format: Cheon Ho Park, Sang Soon Byun, Jin Yong An, Hyerim Han, Weon Sup Lee. PMC-309, a highly selective anti-VISTA antibody reverses immunosuppressive TME to immune-supportive TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5557.
Abstract LB516: MDM2/MDM4 amplification and CDKN2A deletion in melanoma brain metastases and GBM may have implications for targeted therapeutics and immunotherapy
Authors: Taylor E. Arnoff, Wafik S. El-Deiry
Journal: Cancer Research (2022)

Abstract Melanoma has a five-year survival rate of 27% for distant metastatic disease, and there remains a paucity of targeted therapies for metastatic disease and biomarkers that predict metastasis to specific sites. We analyzed 1081 primary melanoma samples and 358 metastatic melanoma samples and found that metastatic disease is enriched for amplifications in both MDM2 and MDM4 compared to primary disease, and these amplifications are associated with a lower probability of overall survival. Two additional negative regulators of TP53, namely USP7 and PPM1D, are enriched for alterations in metastatic melanoma compared to primary melanoma. MDM4 amplifications are associated with a higher rate of metastasis to the brain, liver, and lungs, while MDM2 amplifications are associated with a higher rate of metastasis to the brain, liver, and adrenal glands. These findings suggest that patients with metastatic melanoma show an enhanced dysregulation of the TP53 pathway compared to primary disease; though still under ongoing preclinical evaluation to assess therapeutic implications, we propose that patients with metastatic melanoma and TP53 wild-type status may be more likely to benefit from MDM2, MDM4, USP7, and PPM1D inhibitors, both alone and in combination, compared to those with primary disease. Additionally, we found that patients with MDM2 alterations were more likely to have a deep deletion in CDKN2A, alterations that are also associated with a higher rate of metastasis to the brain. We found that patients with a CDKN2A deep deletion had a statistically significant higher rate of alterations in TTN, MUC16, LRP1B, NF1, and SERPINB4, alterations that have all been previously associated with a favorable response to immune checkpoint inhibitors in melanoma. We therefore propose that CDKN2A deletion may serve as a biomarker to predict response to immunotherapy in melanoma. Moreover, given prior documented cases of patients diagnosed with both melanoma and glioblastoma multiforme (GBM), we found that GBM displays the highest rate of deep deletions in CDKN2A (54.39%) across all cancer types screened. We analyzed 619 GBM samples and found that 9.16% display an MDM2 amplification and 9.52% display an MDM4 amplification. Given the genomic similarities between melanoma and glioblastoma, we suggest that patients with melanoma or GBM and amplifications in MDM2/4 and CDKN2A deletions may need the development of combinations of targeted inhibitors of MDM2/4, CDK’s and immunotherapy. We are currently pursuing these translational directions. Citation Format: Taylor E. Arnoff, Wafik S. El-Deiry. MDM2/MDM4 amplification and CDKN2A deletion in melanoma brain metastases and GBM may have implications for targeted therapeutics and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB516.
Abstract 1226: A genome wide pharmacological perturbation platform
Authors: Cristina Correia, Choong Yong Ung, Cheng Zhang, Scott H. Kaufmann, Hu Li
Journal: Cancer Research (2022)

Abstract Background: Large scale genetic perturbations screens have been instrumental for many key discoveries. In the last decade sequence specific genetic perturbations created RNAi and CRISPR (PMID: 25446316). Recently, specific genome targeting approaches using single guide RNAs (sgRNAs) for the CRISPR-Cas9 system have been repurposed to induce sequence-specific repression or activation of gene expression at a genome-wide scale. Different perturbation approaches have different effects and encompass a trade-off between specificity and duration in establishing a measurable perturbation which can result in different biological readouts. However, bench-side strategies are time consuming and expensive. The method described here aims to build a systems-based computational platform to assess pharmacological and biological perturbations at genome-wide network level.Methods: Our network tool NetDecoder (Nucleic Acids Res. 2016; 44(10):e100) that models genome-wide information flow will be used to build context specific protein-protein interaction networks. These networks will be subsequently subjected to in silico perturbations and their impacts on network properties will be assessed. AVANA and Demeter datasets will be used during method validation procedures. Results: Using publicly available expression datasets we generated context specific Breast Cancer networks and individually manipulated nodes and edges of context-specific networks associated with pharmacological FDA approved targets. Our perturbation networks captured cellular rewiring by engulfing new gene players, alterations of the network size and its connectivity. Conclusions: Our in-silico genome wide perturbation platform provides a flexible approach to fine-tune single and tandem manipulations, allowing for inexpensively monitoring a range of pharmacological interventions using large omics data. Citation Format: Cristina Correia, Choong Yong Ung, Cheng Zhang, Scott H. Kaufmann, Hu Li. A genome wide pharmacological perturbation platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1226.
Abstract 6131: Harnessing resveratrol-mediated restoration of MHC-I in melanoma to enhance immunotherapy
Authors: Lauren C. Morehead, Brian S. Koss, Isabelle R. Miousse, Alan J. Tackett
Journal: Cancer Research (2022)

Abstract The introduction of immunotherapy has drastically improved outcomes in cancer therapy, particularly in melanoma, the deadliest form of skin cancer. However, around half of melanoma tumors are initially resistant to treatment and a significant proportion of initial responders gain resistance later. This is in part because tumors are able to decrease their ability to be recognized by T-cells, an essential actor in immunotherapeutic action. There are two major types of T-cells: CD4+ helper and CD8+ cytotoxic. The most common method used by tumor cells to evade immune attack is to down-regulate major histocompatibility complex (MHC) class I molecules, which allow CD8+ T-cells to recognize cells to be eliminated. Thus, to increase immunotherapeutic efficacy, it is critical to identify how to safely restore MHC-I expression on cancer cells so that tumor antigens are presented to T-cells. I focused on finding potential adjuvants to immunotherapy for this purpose, and I found that resveratrol, a natural compound found in plants and associated with various medicinal properties, consistently elevated MHC-I expression in melanoma cells. Through a proteomics study, I identified that resveratrol also significantly affected pathways known to enhance MHC-I expression. Citation Format: Lauren C. Morehead, Brian S. Koss, Isabelle R. Miousse, Alan J. Tackett. Harnessing resveratrol-mediated restoration of MHC-I in melanoma to enhance immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6131.
Abstract 999: Epigenetic loss of heterogeneity from low to high grade localized prostate tumors
Authors: Ece Sebnem Eksi, Zeynep Sayar, Alex Chitsazan, George T. Thomas, Andrew Adey, Paul T. Spellman, Ryan Kopp
Journal: Cancer Research (2022)

Abstract Identifying precise molecular subtypes attributable to specific stages of localized prostate cancer has proven difficult due to high levels of heterogeneity. Bulk assays represent a population-average, which mask the heterogeneity that exists at the single-cell level. In this work, we sequenced the accessible chromatin regions of 14,424 single-cells from 18 flash-frozen prostate tumors. We observe shared chromatin features among low-grade prostate cancer cells are lost in high-grade tumors. Despite this loss, high-grade tumors exhibit an enrichment for FOXA1, HOXB13 and CDX2 transcription factor binding sites, indicating a shared trans-regulatory program. We identify two unique genes encoding neuronal adhesion molecules that are highly accessible in high-grade prostate tumors. We show NRXN1 and NLGN1 expression in epithelial, endothelial, immune and neuronal cells in prostate cancer using cyclic immunofluorescence. Our results provide a deeper understanding of the active gene regulatory networks in primary prostate tumors, critical for molecular stratification of the disease. Citation Format: Ece Sebnem Eksi, Zeynep Sayar, Alex Chitsazan, George T. Thomas, Andrew Adey, Paul T. Spellman, Ryan Kopp. Epigenetic loss of heterogeneity from low to high grade localized prostate tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 999.
Abstract 3249: Targeting polyploid giant cancer cells to overcome resistance to PARP inhibitors in ovarian cancer
Authors: Xudong Zhang, Jun Yao, Xiaoran Li, Na Niu, Yan Liu, Anil K. Sood, Jinsong Liu
Journal: Cancer Research (2022)

Abstract PARP inhibitors (PARPi) offer major clinical benefit for patients with ovarian or other cancers, especially those with deficiencies in the homologous recombination DNA repair pathway. However, most patients with advanced cancer eventually acquire resistance to PARPi, and the mechanisms by which tumors escape PARPi therapy are still not fully understood. Here, we report that treatment with the PARPi olaparib induces the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines (Hey, SKOV3, MCF-7), three human high-grade serous cancer (HGSC)-derived organoids, and HGSC patient-derived xenografts. Live-cell fluorescence time-lapse tracking of ovarian cancer cells labeled with FUCCI (fluorescent ubiquitination cell-cycle indicator) or histone H2B-mCherry/α-tubulin-EGFP revealed that PGCCs primarily developed from the endoreplication of diploid cancer cells after exposure to sublethal concentrations of olaparib. PGCCs exhibited markers of senescent cells; however, they were able to escape senescence to generate mitotically competent daughter cells via budding, multipolar mitosis, and acytokinetic mitosis following olaparib withdrawal. PGCCs and derived daughter cells conferred resistance to olaparib-induced cytotoxicity, which could be blocked by the anti-progesterone drug mifepristone. Whole transcriptome analysis by RNA sequencing of ovarian cancer cell lines and ovarian cancer-derived organoids showed activation of a senescence-associated secretory phenotype with upregulated cytokines and chemokines and downregulation of MYC signaling in PGCCs. Mifepristone/olaparib combination therapy significantly mitigated tumor growth in patient-derived xenograft models with acquired resistance to olaparib. Thus, targeting of PGCCs may represent a promising approach to overcome PARPi resistance in recurrent ovarian cancer. Citation Format: Xudong Zhang, Jun Yao, Xiaoran Li, Na Niu, Yan Liu, Anil K. Sood, Jinsong Liu. Targeting polyploid giant cancer cells to overcome resistance to PARP inhibitors in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3249.